The ras gene family code for a membrane protein p21 closely related to the G-protein family of a membrane signal transduction pathway. Studies were carried out to understand the role of ras proteins in phosphoinositide (PI) metabolic pathway triggered by growth factors. PDGF stimulates PI turnover in normal rat kidney (NRK) cells and enhances hydrolysis of phosphoinositol monophosphate and bisphosphate (PIP2) in NRK cell membrane in the presence of GTPrs. Pertussis toxin does not inhibit the stimulatory effect of PDGF on PIP2 hydrolysis, suggesting that PDGF-stimulated phospholipase C activity is controlled by a G-protein which is different from Gi or Go. In contrast, the response to PDGF is completely lost in ras transformed cells, with the transformed cells showing a higher basal level on PI turnover than NRK cells. Using bacterially made normal or oncogenic T24 ras protein, we investigated the effect of ras proteins on inositol trisphosphate (IP3) production of NRK cell membrane in vitro. Normal ras protein increases the formation of IP3, whereas T24 ras protein dose not have a significant effect. Moreover, normal ras protein and PDGF have additive effects on IP3 production. Our results indicate that normal ras protein may be coupled, indirectly or directly, with PDGF-stimulated phospholipase C activity and that oncogenic ras protein appears to be defective in this coupling. These findings are of considerable interest, implying the important regulatory role for ras proteins in cell transformation mechanisms.